Combined Hormone Replacement in Menstrually-Related Mood Disorders

Results from previous protocols (#90-M-0088 and 92-M-0174) have demonstrated that women with
menstrually-related mood disorder (MRMD), but not women lacking this disorder, experience
mood deterioration within approximately a week after exposure to either estradiol or
progesterone in the context of gonadal suppression (induced by use of the depot gonadotropin
releasing hormone agonist, leuprolide acetate). It is unknown whether this hormone-induced
depression occurs consequent to changes in gonadal steroid levels or to simple exposure to
levels above a critical threshold. Additionally, since the symptoms of depression stimulated
by hormone addback appeared to remit by the fourth week of hormone administration, it is
unclear whether continued administration of hormone would result in continued or repeated
experience of depression or whether no further symptoms would appear subsequent to the
initial precipitated episode. To address these points of uncertainty, we first will establish
the efficacy of gonadal suppression in our MRMD subjects by administering depot leuprolide
acetate for three months and then will administer both estradiol and progesterone in a
continuous fashion for three months to determine whether maintenance of stable gonadal
steroid levels will prevent the characteristic cyclic mood disorder.

- INCLUSION CRITERIA:

The subjects of this study will be women who meet the criteria for MRMD as described in
Protocol # 81-M-0126, The Phenomenology and Biophysiology of Menstrually-related Mood and
Behavioral Disorders. In brief, these criteria include the following:

1. History within the last two years of at least six months with menstrually-related mood
or behavioral disturbances of at least moderate severity--i.e., disturbances that are
distinct in appearance and associated with a notable degree of subjective distress and
interference with life activities;

2. Symptoms with a sudden offset and absence of significant symptomatology during the
follicular phase;

3. Age 18-50;

4. Regular menstrual cycles (21-35 days in length), not pregnant, and in good medical
health;

5. Not pregnant;

6. In good medical health;

5) Medication free.

All patients participating in this protocol will have already participated in Protocol No.
81-M-0126 and will have a prospectively confirmed and predictable relationship between
their mood disorder and the premenstrual phase of the menstrual cycle; i.e., a 30% change
in severity of symptom self rating scales, relative to the range of the scale employed,
during the seven days premenstrually compared with the seven days post-menstrually in two
out of three months of study. This method formed the basis of the NIMH PMS Workgroup
diagnostic guidelines and produces results that are highly convergent with the effect size
method for diagnosing PMS.

All subjects will be required to use non-hormonal forms of birth control (e.g. barrier
methods with the exception of IUD s) to avoid pregnancy during this study.

EXLUSION CRITERIA:

The following conditions, also, will constitute contraindications to treatment with
hormonal therapy and will preclude a patient's participating in this protocol:

1. Current Axis I psychiatric diagnosis

2. History of endometriosis;

3. Diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian
enlargement;

4. Hepatic disease as manifested by abnormal liver function tests;

5. History of mammary carcinoma;

6. History of pulmonary embolism or phlebothrombosis;

7. Undiagnosed vaginal bleeding;

8. Porphyries;

9. Diabetes mellitus;

10. History of malignant melanoma;

11. Cholecystitis or pancreatitis;

12. Cardiovascular or renal disease;

13. Pregnancy;

14. Significant clinical or laboratory abnormalities